A method of treating cystic fibrosis

Abstract

Described herein are methods and compositions related to vectors, including but not limited to a method for treating cystic fibrosis (CF) using adeno-associated vims (AAV) particles, using a catheter to administer a population of viral vectors to a plurality of target sites in a subject by bronchial artery catheterization delivery.

1 . A method for treating cystic fibrosis (CF) comprising:
 administering a population of vectors to a plurality of target sites in a subject wherein the vector contains a therapeutic nucleic acid, and wherein the vectors are administered by bronchial artery catheterization delivery comprising,   placing a catheter into a first bronchial artery and administering a first dose of vector into the catheter to target basal laminar target sites in the family of bronchioles subtended by said bronchial artery,   and placing the same or different catheter into at least a second bronchial artery to target a second family of bronchioles containing a second population of basal lamina cells.   
     
     
         2 . The method of  claim 1 , further comprising placing the same or different catheter into a third bronchial artery to target a third family of bronchioles containing a third population of basal lamina cells; and
 if needed further comprising placing the same or different catheter into a fourth bronchial artery to target a fourth family of bronchioles containing a fourth population of basal lamina cells; and   if needed further comprising placing the same or different catheter into a fifth bronchial artery to target a fifth family of bronchioles containing a fifth population of basal lamina cells.   
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the first dose is proportional to the first bronchial artery volume and the second dose is proportional to the second bronchial artery volume. 
     
     
         6 . The method of  claim 1 , wherein a first dose of vector is administered into the catheter to target the first basal lamina target site of a basal/progenitor cell, a club cell, or a ciliated cell in a first set of bronchioles. 
     
     
         7 . The method of  claim 1 , wherein the therapeutic nucleic acid is a therapeutic Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, or is a truncated therapeutic Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, or a gene editing molecule. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 7 , wherein the truncated therapeutic Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene can specifically rescue the processing of ΔF508-CFTR. 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the vector is a viral vector. 
     
     
         13 . The method  claim 12 , wherein the viral vector is selected from any of: an adeno-associated virus (AAV), adenovirus, lentivirus vector, or a herpes simplex virus (HSV). 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 7 , wherein the gene editing molecule is selected from a nuclease, a guide RNA (gRNA), a guide DNA (gDNA), and an activator RNA. 
     
     
         17 . The method of  claim 7 , wherein at least one gene editing molecule is a gRNA or a gDNA. 
     
     
         18 . The method of  claim 17 , wherein the guide RNA targets a pathology-causing CFTR mutation and/or is selected from Table 4. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 16 , wherein the nuclease is a sequence specific nuclease selected from a nucleic acid-guided nuclease, zinc finger nuclease (ZFN), a meganuclease, a transcription activator-like effector nuclease (TALEN), or a megaTAL, a nucleic acid-guided nuclease selected from a single-base editor, an RNA-guided nuclease, and a DNA-guided nuclease 
     
     
         21 . The method of  claim 20 , wherein the sequence specific nuclease is a nucleic acid-guided nuclease selected from a single-base editor, an RNA-guided nuclease, and a DNA-guided nuclease, and or the nucleic acid-guided nuclease is a CRISPR nuclease. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 21 , wherein the CRISPR nuclease is a Cas nuclease. 
     
     
         25 . The method of  claim 1 , wherein
 a) the bronchial artery delivery is accompanied by a pulmonary wedge pressure catheterization and measurement; and/or   b) the proximity to the target site is 5 to 10 microns.   
     
     
         26 . The method of  claim 25 , wherein:
 a) the population of viral vectors is administered by slow infusion over one to thirty minutes; and/or   b) pressure is applied to the respiratory reservoir bag every second to fifth breath for up to fifteen seconds in periodic or pulsed intervals during infusion.   
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 26 , wherein:
 a) the pressure is supplied every second to fifth breath for up to 15 seconds; and/or   b) the pressure is 2-15 mmHg.   
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 1 , wherein the vector is an AAV particle comprising a capsid encapsidating a nucleic acid sequence containing at least one pair of AAV ITRs flanking a segment encoding CFTK operably linked to a promoter, and wherein the capsid comprises at least one capsid protein selected from the group consisting of VP1, VP2, and VP3, that are each from the same or different AAV serotype. 
     
     
         32 . The method of  claim 31 , wherein the at least one capsid protein is from a serotype selected from the group consisting of AAV serotype 1, AAV serotype 2, AAV serotype 3, AAV serotype 3A, AAV serotype 3B, AAV serotype 4, AAV serotype 5, AAV serotype 6, AAV serotype 7, AAV serotype 8, AAV serotype 9, AAV serotype 10, AAV serotype 11, AAV serotype 12, AAV serotype 13, avian AAV, bovine AAV, canine AAV, equine AAV and/or ovine AAV. 
     
     
         33 . (canceled) 
     
     
         34 . The method of  claim 32 , wherein the at least one capsid protein is from AAV serotype 9. 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . (canceled)